Type 2 diabetes mellitus (T2D) affects 18 million Americans, with national healthcare and lost productivity costs exceeding $100 billion per year. T2D begins as a state of compensated insulin resistance;frank disease develops when approximately 50% of insulin-producing pancreatic islet [unreadable]-cells of affected individuals undergo cell death. Numerous recent studies link T2D to endoplasmic reticulum (ER) stress, a condition that occurs whenever protein folding requirements overwhelm protein-folding capacity in the secretory pathway. Notably, there is mounting evidence that ER stress contributes to diminished glucose-responsive insulin secretion in [unreadable]-cells, to [unreadable]-cell apoptosis, and to general peripheral insulin resistance, all hallmarks of T2D. ER stress triggers the unfolded protein response (UPR) pathway, which slows translation and transcriptionally upregulates genes that enhance ER protein-folding capabilities. If homeostasis is not restored through these outputs, the UPR triggers apoptosis instead. We hypothesize that a key component of the UPR, Ire1a, acts as a toggling switch between homeostatic and apoptotic outputs, ultimately controlling [unreadable]-cell fate. The project goal of this STTR is to identify a small molecule that biases Ire1a.s outputs towards homeostasis and evaluate its therapeutic potential by demonstrating cytoprotective effects in [unreadable]-cell-derived cell lines. We have developed a novel biochemical assay to detect such compounds, with hits already identified. Structure-based design will guide our medicinal chemistry to provide increasingly potent cytoprotective agents. Results from the proposed studies will guide our selection of lead compounds to validate this approach in disease-relevant animal models of [unreadable]-cell function and capacity. Ultimately, these studies represent significant early steps to develop a novel, oral treatment for the improvement of glycemic control in type 2 diabetics with the unique potential to modify disease progression.